One drug, mipomersen, gained a tepid endorsement with a 9-6 vote Thursday, and a day earlier the same panel -- the Endocrinologic and Metabolic Drugs Advisory Committee -- signaled stronger favorable sentiment voting 13-2 for approval of lomitapide as adjuvant therapy for HoFH and other severe lipid disorders.

The agency usually follows the recommendations of its advisory panels, although it is not required to do so.

Mipomersen's maker, Cambridge, Mass.-based Genzyme, is seeking an indication to treat HoFH as an adjunct to maximally tolerated lipid-lowering medications.

HoFH is a rare genetic condition that if untreated can cause extremely high cholesterol levels, typically between 400 mg/dL and 1,000 mg/dL. It affects roughly one in 1 million people in the U.S.

On Thursday members of the FDA's advisory panel -- those who supported and opposed approval -- expressed concern about mipomersen's safety profile but were swayed by testimony that argued doctors needed new tools to treat the rare disease.

The drug was studied in four phase III, randomized, double-blind, 6-month trials, and 18% (47 of 261) of patients treated with mipomersen dropped out of studies because of adverse events.

Reasons for discontinuing the trial included injection site infections, which afflicted 84% of mipomersen patients. The drug is delivered once-weekly via subcutaneous injection. Advisory committee members also expressed concern over liver toxicity.

Nonetheless, mipomersen patients achieved an average 24.7% decrease in LDL compared with a decline 3.3% of placebo patients.

However, the agency called into question the use of LDL as a surrogate endpoint for the ultimate goal of reducing cardiovascular disease. "There was no evidence for a decrease in cardiovascular events in the mipomersen group as compared to the placebo group in these trials," the FDA said in briefing documents released ahead of Thursday's meeting.

The safety concerns and efficacy questions didn't sway support for the treatment of a severe condition for patients with a poor quality of life.

"Even if a third of the group benefits, that should be viewed as a win," Edward Gregg, PhD, chief of epidemiology in the division of diabetes translation at the CDC in Atlanta, said during the meeting.

The FDA in its briefing documents proposed a risk evaluation and mitigation strategy (REMS) that would require all prescribers and pharmacies to achieve special certification. Prescribers would be educated on the approved indication, potential risks, and the need to monitor patients during treatment per the drug's labeling.

The FDA has a date of Jan. 29 for deciding whether to approve the drug.

The same panel on Wednesday voted 13-2 to recommend approval for the new drug lomitapide to treat certain severe lipid disorders, including HoFH, when used as an adjunct to a low-fat diet and other lipid-lowering therapies.

The once-daily capsule inhibits a particular protein which reduces the cholesterol that the liver and intestines assemble and secrete into the bloodstream. Right now, there is no such inhibitor approved by the FDA.

While statins are the standard method for treating high cholesterol, people with HoFH lack LDL receptors -- a deficiency which lowers statins' efficacy.

Lomitapide lowered LDL from an average of 336 mg/dL at the start of a 26-week trial to 190 mg/dL, a drop of more than 40% among the 29 patients in the trial. "There was ... a positive correlation between mean dosage prescribed and observed LDL reduction at the population level," FDA reviewers stated in briefing documents released before the Wednesday meeting.

However, 10% of the 29 patients in the 26-week study had at least one serious adverse event. That percentage rose to 22% during the first 120 days of an extension trial.

Common adverse events included gastrointestinal (GI) disorders such as diarrhea, nausea, vomiting, dyspepsia, and abdominal pain. Bristol-Myers Squibb abandoned development of the drug in 2000 over concerns of GI tolerability.

The FDA recommended a REMS for lomitapide similar to that for mipomersen; it would require all prescribers and pharmacies to achieve special certification.

Lomitapide was developed by Aegerion Pharmaceuticals of Cambridge, Mass. The FDA has set a date of Dec. 29 to decide on whether to approve it.

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